Next-generation crystallography: UB and partner institutions awarded $25 million to develop new X-ray imaging of biomolecules

by jmaloni

Submitted

Wed, Nov 6th 2013 01:00 pm

Powerful laser technique will
dramatically expand the number of drug targets accessible for research and
discovery

The
University at Buffalo, representing a national consortium of eight research
universities and institutes, has been awarded a prestigious $25-million Science
and Technology Center grant from the National Science Foundation to transform
the field of structural biology, including drug development, using X-ray
lasers.

This
is the first Science and Technology Center grant UB has received. With the
grant, UB and its partner institutions will establish The BioXFEL research
center (http://www.bioxfel.org/),
headquartered in Buffalo.

The
BioXFEL (pronounced bio-x-fell) center will focus on developing new X-ray
bioimaging techniques - including an advanced form of X-ray crystallography
called serial femtosecond crystallography - to analyze a vast array of new
molecular targets for drug discovery.

This
technique has the potential to spur much-needed innovation in the
pharmaceutical field. It will provide scientists with new insights into how
biological molecules function, what might be happening when disease occurs, and
what compounds might be designed as drugs to modify this activity.

"Together
with its partners, UB is especially proud to announce this highly competitive
award," said UB President Satish K. Tripathi. "NSF selects just a handful of
Science and Technology Center winners every four years from a pool of hundreds
of applicants. This research builds on Western New York's rich legacy of
expertise in X-ray crystallography, historically based within the
Hauptman-Woodward Medical Research Institute and UB's Department of Structural
Biology."

SUNY
Chancellor Nancy L. Zimpher said, "With this prestigious award, the University
at Buffalo deepens its national leadership and long tradition of groundbreaking
health research and the innovative treatment of disease. Congratulations to
President Tripathi and the team of scientists who have secured this extraordinary
grant."

"Congratulations
to President Tripathi, Professor Lattman and the extraordinary faculty team,"
said Tim Killeen, Ph.D., president of the Research Foundation for SUNY and
SUNY's vice chancellor for research. "This is, without question, the premier
award given out by NSF and truly exciting news for us all. The groundbreaking,
cutting-edge research will, once again, showcase UB's stature as a world-class
research university. The collaborative work conducted through this award
represents a major contribution to Chancellor Nancy Zimpher's vision of the
Power of SUNY and the SUNY Networks of Excellence announced recently by Gov.
Cuomo."

"This
$25-million federal grant demonstrates the strength of Buffalo Niagara Medical
Campus institutions to serve as outliers in science and medical innovation,"
said Rep. Brian Higgins. "Not only will it advance critical research, this
significant investment will advance economic growth in the City of Buffalo."

"This
first of its kind federal investment in the important work being done by
Hauptman-Woodward and the University at Buffalo just proves once again that
Western New York is on the cutting edge of medical and scientific research,"
Schumer said. "This Science and Technology Center grant will not only lead
to important new breakthroughs in drug development - but will also serve as a
signal to new companies around the globe that Buffalo is the place to be when
it comes to medical research."

"This
highly competitive award reflects the University at Buffalo's relevance as an
innovator in the field of medical research and bio-tech," Gillibrand said.
"With these resources, UB will be given the opportunity to make
groundbreaking advancements in the pharmaceutical field, further adding to the
university's contribution to the region's biomedical economy."

Eaton
E. Lattman, Ph.D., professor in the UB department of structural biology in the
School of Medicine and Biomedical Sciences and CEO of the Hauptman-Woodward Medical
Research Institute, will be director of the BioXFEL center.

John
C.H. Spence, Ph.D., Regents' professor of physics at Arizona State University,
will serve as the center's scientific director. The University of Wisconsin-Milwaukee
also will have a primary role in the center, led by principal investigator
Abbas Ourmazd, Ph.D., distinguished professor of physics and electrical
engineering.

Other
partner institutions are Cornell University; Rice University; the University of
California, San Francisco; and Stanford University. The University of
California, Davis, also will help with creating and managing the educational
program.

The
establishment of the BioXFEL center will put UB and Western New York in the
forefront of this technology. "It has the potential to transform the way
scientists study diseases and develop new treatments," said Alexander N.
Cartwright, Ph.D., vice president for research and economic development at UB. "The
late Dr. Hauptman won the Nobel Prize in 1985 with Jerome Karle for the
development of direct methods for determining the structures of molecules. This
new UB center, in partnership with HWI, will take the extraordinary promise of
that 20th-century technique and revolutionize it further for the 21st century."

While
current techniques in crystallography provide almost 90 percent of what
scientists know about biomolecular structure, fewer than 20 percent of purified
proteins currently form the crystals necessary for this technique.

"With the new bioimaging technique developed
in the BioXFEL center, we will be able to analyze crystals 1,000 times smaller
than the ones we can use now," Lattman said. "These are crystals we could never
use before and, in fact, may not have known existed. A whole new universe of
drug targets will become accessible for study as a result."

"In
addition," added Spence, "we will be developing new techniques for making
movies of molecular machines at work, and of viruses and biomolecules in their
natural wet environment undergoing chemical change. Some of the work, with professor
Petra Fromme at ASU, will try to image the detailed atomic processes
responsible for photosynthesis. This occurs when sunlight falls on all green
plants, allowing them to split water, creating the oxygen we breathe and
converting the carbon dioxide responsible for global warming into
carbohydrates."

"The
techniques the BioXFEL center will develop could shorten the process of
determining protein structure from years to days," said Ourmazd of the
University of Wisconsin-Milwaukee. "This will rely heavily on mathematical
algorithms we and others are developing to deduce structure from millions of
ultralow-signal snapshots."

The
new technique enables the study of ultra-small crystals - nanocrystals, Lattman
explained - which grow much more readily than the much larger ones required by
current methodology.

"Many
other aspects of the project, such as the patterns created by the X-ray laser,
are different from what we are used to," he said. "We have to figure out how to
work with them, both experimentally and theoretically."

He
noted that the new technique offers tantalizing possibilities in the future.
"Maybe down the road, we won't even use crystals at all, but we're a long way
away from that," he said.

Scientists
involved with the BioXFEL center will use an extremely powerful new kind of
X-ray beam developed at SLAC National Laboratory at Stanford University called
an X-ray, free-electron laser. The use of the XFEL to analyze protein crystals
was chosen by the journal Science as one of the top 10 science breakthroughs of
2012. That work included a number of scientists who will be participants in the
BioXFEL center.

"Because
this technique is so new, much remains to be done before it can be used
routinely," explained Lattman. "The process needs to be streamlined. Right now,
every single step takes a heroic effort. The purpose of the new BioXFEL center
is to create the resources and knowledge necessary so that, five years from
now, scientists can apply XFEL routinely to the most pressing biomedical
questions."

A
key advantage is that it will let scientists see the motions of molecules for
the first time. "Most biological processes require movements within the
molecules involved," Lattman said, "but the pictures provided by current X-ray
analysis contain very limited information about them.

"The
XFEL beam is unbelievably intense and is composed of a sequence of unimaginably
short pulses that act like flashbulbs to freeze the motions of protein
molecules when the beam zaps them," Lattman added. "In the long run, the X-ray
laser will allow us to make movies of molecules, rather than having to infer
their motions from fixed pictures."

HWI
expertise will play a central role in the new center, particularly its National
Institutes of Health-funded high-throughput screening laboratory, which has
been growing crystals of proteins for hundreds of client labs throughout the
U.S. for a decade.

Arizona
State will be a major research partner, providing expertise through Spence's
lab, which specializes in determining the structures of membrane proteins and
viruses, which are difficult to crystallize. University of Wisconsin-Milwaukee will
provide key theoretical and experimental contributions.

Together,
UB, Arizona State and UWM will offer education programs to try to develop young
scholars in this technique at the graduate and postdoctoral level, as well as
the undergraduate and high school levels. Lattman said UB will be one of the
key facilities in the U.S. with this focus.

The
center will emphasize applications of its research through its industrial
partners in the Industrial Macromolecular Crystallography Association comprised
of major pharmaceutical companies, including Bristol-Myers Squibb, Pfizer,
Abbott, Merck and Novartis.

The
BioXFEL center's headquarters will be located at 700 Ellicott St., on the
Buffalo Niagara Medical Campus, in the building that houses both HWI and UB's
Department of Structural Biology.

The
NSF Science and Technology Centers: Integrative Partnerships program supports
innovative, potentially transformative research and education projects that
require large-scale, long-term awards. The centers foster cutting-edge
research, education of the next generations of scientists and broad
distribution of the knowledge and technology produced.